Plasma Free Normetanephrine Research Articles

5179 Uncommon Benign Mimics Of Suspicious Adrenal Nodules

Abstract Disclosure: L. Zhu: None. L. Loh: None. V. Gan: None. P. Kek: None. Introduction: Adrenal incidentaloma is often detected in imaging studies. In addition to biochemical testing, imaging plays a key role in guiding the management of such lesions. We describe two uncommon cases of benign lesions masquerading as suspicious adrenal nodules. Case 1. A 54-year-old man with hypertension, diabetes, dyslipidaemia, ischaemic heart disease and atrial fibrillation (on warfarin) underwent CT scan to exclude malignancy when he presented with thigh DVT, and was found to have a right 3.2cm adrenal nodule. Adrenal hormone profile was unremarkable. CT contrast characterization showed attenuation of 30, 35, and 32 HU on pre-contrast, venous and 10-minute delayed phase respectively. Given the minimal enhancement in high density areas, possible haemorrhage was considered and he was put on imaging surveillance. CT scans over the following 5 years showed stability of the lesion, resolution of high-density areas, and pre-contrast attenuation of -35HU, suggestive of myelolipoma. Further follow-up over the next 2 years then revealed tumour enlargement to 8.5cm, progressive predominance of dense areas (58 HU), and development of compressive symptoms. In view of mass effect, growing heterogeneity and possibility of a collision tumour, right adrenalectomy was performed. Histopathology revealed myelolipoma with extensive haemorrhage and no evidence of malignancy. Case 2. A 65-year-old woman had hypertension, ischaemic heart disease, dialysis-dependent end-stage renal disease secondary to glomerulonephritis, and oncological history of left renal cell carcinoma (RCC) and low-grade papillary urothelial carcinoma, both surgically resected 10 years ago. A new 1.6cm right adrenal nodule was seen on her surveillance CT scan for RCC. It was not present in a CT scan 7 years ago. The nodule displayed suspicious features such as nodular avid rim enhancement, persistent enhancement on delayed phase of contrast washout and central cystic change. Biochemical screening revealed plasma free metanephrine of 0.33 nmol/L (NR: <0.33) and plasma free normetanephrine of 0.99 nmol/L (NR: <0.71). Other adrenal hormone profiles were unremarkable. Cystic phaeochromocytoma was suspected and she underwent right adrenalectomy and nephrectomy following alpha blockade. Histopathology revealed a well-circumscribed nodule in the supra-renal adipose tissue, with vascular proliferation and features of anastomosing haemangioma. The right kidney was reported to have acquired cystic disease associated RCC. She was well post-operatively and remained on follow-up with the urologist for her RCC. Discussion: Haemorrhagic adrenal myelolipoma and supra-renal anatomosing haemangioma are benign lesions that may have CT characteristics similar to those of sinister lesions. Pre-operative diagnosis can be challenging. Surgical excision may be required to confirm diagnosis and exclude malignancy. Presentation: 6/3/2024

Is It Enough to Diagnose Pheochromocytoma by Measuring Urine Metanephrines Levels?

This study aimed to evaluate the diagnostic value of plasma and urinary metanephrines and determine their sensitivity, specificity, and correlation among patients with adrenal lesions, which required a multidisciplinary approach because of size, functional state, or malign appearance. This retrospective study of 152 patientswith adrenal lesions was conducted at the Outpatient Clinics of Ankara Bilkent City Hospital at the Department of Endocrinology and Metabolism Diseases betweenAugust 2019and February 2022. These patients were discussed at the Endocrinology and Surgery multidisciplinary council because of their adrenal lesions.Among them, 94 patients underwent adrenal surgery. Thirty patients with histologically proven pheochromocytoma, 36 with cortical nodular hyperplasia, four cases of adrenocortical carcinoma and 24 cases with angiomyolipoma were detected. According to the analysis, the most sensitive test in diagnosing pheochromocytoma was urinary fractionated metanephrine (90%), followed by plasma free metanephrines at 84 %. Conversely, the most specific test was plasma free normetanephrine (91.4%).A statistically significant correlation exists between plasma and urinary metanephrine; plasma normetanephrine levels were alsosignificantly correlated with urine normetanephrine. These findings indicate that plasma and urine metanephrines are sensitive for detecting pheochromocytoma and can be used interchangeably.

SAT312 CT-guided Cryoablation Of Hereditary Pheochromocytoma

Abstract Disclosure: E. Griffing: None. B. Reading: None. F. De Luca: None. Background: Guidelines surrounding the management of hereditary pediatric pheochromocytomas (PHEO) are lacking. This is the first report of a pediatric patient with bilateral hereditary PHEO treated with right adrenalectomy and computed tomography (CT) percutaneous-guided cryoablation (CRA) of the left-sided lesion.Clinical case: A previously healthy 15 years-old male presented to a tertiary care hospital with a months-long history of episodic chest pain, flushing, shortness of breath, diaphoresis, and tremulousness. Paternal family history was significant for PHEO and brain stem hemangioblastoma in grandmother and PHEO in the great-grandfather. Targeted familial mutation analysis of the von Hippel-Lindau tumor suppressor gene was positive for pathogenic mutation c.500G>A (p.R167Q). Plasma free normetanephrine level was 4,625 pg/mL (nl: <145 pg/mL), while free metanephrines were normal. Magnetic-resonance imaging of the abdomen visualized a 4.4 x 3.4 x 5.3 cm right adrenal mass and a 1.4 x 1.4 x 1.4 cm left adrenal mass, consistent with bilateral PHEO. He underwent right adrenalectomy after initiation of alpha-receptor blockade and later addition of beta-receptor blockade due to heart rates in the 150’s. After discussion with parents, it was decided to observe the smaller left-sided adrenal lesion. Plasma free normetanephrines initially decreased to 338 pg/mL, but then increased to 507 pg/mL five months post-operatively. Six months after surgery, due to the persistence of hypertension with systolic blood pressure in the 140’s as well as tachycardia with heart rates in the 150’s, he underwent CT-guided CRA of the left-sided PHEO. A 12-minute freeze, 5-minute thaw, and 10-minute freeze, followed by an active thaw were performed. There was an increase in blood pressure during the initial thaw with systolic blood pressure in the 230s, accompanied by bradycardia to the 30s, treated with nitroprusside, phentolamine, and increased sedation. He required continuation of nitroprusside infusion for five hours post-procedure. He was discharged the following day with normal blood pressure and heart rate. He was able to completely wean off anti-hypertensive medications within one month and symptoms of chest pain and tachycardia resolved. In the four years since his procedure, he has not had a recurrence of PHEO nor development of adrenal insufficiency. Plasma free normetanephrines and metanephrines have remained within normal limits. Conclusion: Percutaneous ablation of hereditary PHEO has not been reported before in the pediatric population and may represent a novel treatment strategy that reduces the risk of adrenal insufficiency. Presentation: Saturday, June 17, 2023

SAT561 Pathogenic RET V804M Germline Variant Without Clinical Manifestations Of Multiple Endocrine Neoplasia Type 2 In An Elderly Male

Abstract Disclosure: R. Ghosh: None. G. Al-Naqeeb: None. P. Veeraraghavan: None. C. Craig: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Germline pathogenic variants in the RET protooncogene give rise to multiple endocrine neoplasia (MEN) types 2A and 2B. MEN2A is mainly characterized by MTC (∼100%), pheochromocytoma (PHEO; 4% - 88%), and primary hyperparathyroidism (HPTH; 2% - 30%), while MEN2B predominantly manifests with MTC (100%), PHEO (50%), mucocutaneous neuromas, and marfanoid habitus. Both MEN2A and 2B follow an autosomal dominant mode of inheritance. While certain pathogenic RET variants (M918T, A883F, and C634X) have high penetrance and present with aggressive disease, other variants such as V804M are of low penetrance and manifest with clinically mild disease.Clinical case: A 75-year-old male was referred to our center for further evaluation of the finding of an abnormal RET gene that was identified on a peripheral blood whole-exome gene sequencing research panel performed at an outside center. The patient was noted to have a germline RET c.2410 G>A, p.V804M heterozygous pathogenic variant. The patient denied any history of lump in the neck, symptoms of hyper- or hypothyroidism, tremors, headaches, fatigue, facial flushing, palpitations, constipation, diarrhea, anxiety, depression, or history of fragility fractures. Medical history consisted of hypertension, nephrolithiasis, type 2 diabetes mellitus, obstructive sleep apnea, interstitial pulmonary fibrosis, and colonic diverticula and polyps. Family history was significant for leukemia, colon, and breast cancers, but none of the relatives had a history of MTC, PHEO, or MEN2, and his children, while healthy, had not undergone RET germline testing. Physical examination showed no evidence of hypothyroidism or hyperthyroidism. Neck examination showed no evidence of thyromegaly or cervical lymphadenopathy. Laboratory investigations were unremarkable [serum calcitonin: 7.9 pg/ml (NL: </=14.3), CEA 2.8 mcg/L (NL: 0.8-3.4), thyrotropin (TSH): 1.92 microIU/ml (NL: 0.35-4.94), free thyroxine: 0.9 ng/dl (NL: 0.7-1.5), plasma free normetanephrine: 0.31 nmol/L (NL: <0.9), plasma free metanephrines 0.24 nmol/L (NL: <0.5), parathyroid hormone: 28.2 pg/ml (NL: 15-65), and ionized calcium 1.23 mmol/l (NL: 1.09-1.30)]. Thyroid sonogram was normal. We recommended active annual surveillance with biochemical markers and imaging along with genetic testing of the RET gene in his children. Conclusion: The V804M RET variant has been often associated with MTC or MEN2A phenotypes [1]. However, the variable expression of this variant may lead to a mild clinical phenotype or even absence of MTC/MEN2A manifestations. Hence, active surveillance as opposed to radical surgery like prophylactic thyroidectomy would be more beneficial in patients with no clinical or biochemical evidence of disease. Reference: Pinna et al., 2007, V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype. Thyroid, 17(2), 101-104. Presentation Date: Saturday, June 17, 2023

FRI270 A Rare Case Of Giant Benign Pheochromocytoma

Abstract Disclosure: M.S. Hossain: None. B. Gautam: None. K. Mandal: None. H. Liao: None. D.S. Rosenthal: None. S.C. Kumar: None. Background: Pheochromocytomas are Catecholamine-secreting tumors that arise from the adrenal medulla. These tumors are rare however giant pheochromocytomas (>7 cm) are even rarer entities, which are thought to be more aggressive and malignant. Here we present a case of incidentally found giant but benign pheochromocytoma. Case Report: A 40-year-old female with no PMH presented to the hospital with fever & cough for 1 month which was associated with weight loss (10lb). Patient was started on antibiotics and CT revealed right-sided adrenal incidentaloma while searching for sources of infection. CT & MRI abdomen were done for better characterization, showed a round circumscribed right adrenal mass measuring 11.3 x 11.4 x 12.8 cm. Mass had irregular central necrosis, peripheral enhancement & neovascularization. Patient denied headache, sweating & palpitation; no personal or family history of pheochromocytoma. On physical examination BP: 103/70, HR: 98, Temp: 98F, BMI:25.9, unremarkable for cushingoid features, virilization & hirsutism. Hormonal workup showed elevated free normetanephrine 185 (<148pg/ml) & chromogranin A 801 (<311ng/ml), but normal free metanephrine <25 (<57pg/ml) & total metanephrines 185 (<205pg/ml). 24hr Urine study: elevated total metanephrines 1661 (182-739mcg/24h) & normetanephrine 1482 (88-649mcg/24h) but normal metanephrine 179(58-203mcg/24h), urine volume 2360ml/24h, urine creatinine 0.87(0.50-2.15g/24h). Patient Cortisol, ACTH, Aldosterone, Renin activity, DHEA-S, Androstenedione was normal. Patient was started on alpha-blockers. Patient underwent successful right-sided adrenalectomy & nephrectomy with IVC resection. Pathology reported pheochromocytoma stage II T2Nx, Ki 67 <5%. No vascular and extracapsular invasion & no mitosis. Post operative outpatient follow up showed elevated plasma free normetanephrine 199(<148pg/ml) & normal free metanephrine <25 (<57pg/ml) & total metanephrine 199 (<205pg/ml). 24hr urine study: normal metanephrine 61 (58-203mcg/24h), Normetanephrine 268 (88-649mcg/24h) & total metanephrines 329 (182-739mcg/24h). Patient was advised for Ga68 DOTATE/PET scan, genetic counseling & lifelong follow-up with endocrinology for surveillance. Discussion: Pheochromocytoma symptoms may vary regardless of tumor size. Giant pheochromocytoma may not have high secretory potential due to central necrosis resulting in reduced chromaffin cells or catecholamines that are restricted to capsular mass which may release into the bloodstream intraoperatively1. Therefore, initiating alpha-blockers before surgery in these cases may prevent perioperative complications.1. Minei S, Yamashita H, Koh H, Satoh T, Kobayashi S, Furuhata M, et al. Giant cystic pheochromocytoma A case report. Hinyokika Kiyo. 2001;47:561-3. Presentation: Friday, June 16, 2023

Plasma-free metanephrines, nerve growth factor, and renalase significance in patients with PCOS.

Polycystic ovarian syndrome (PCOS) is a common heterogeneous condition with probably multifactorial genesis. Animal studies have proven the essential role of the sympathetic nervous system in the syndrome development, while human studies are still contradictory. The present study aims to investigate the possible influence of plasma-free metanephrine (MN), and normetanephrine (NMN), nerve growth factor (NGF), and renalase (RNL) on the hormonal and metabolic parameters in women with PCOS and healthy controls. Fifty patients with PCOS and 30 healthy women participated in the study. The plasma-free MN and NMN, NGF, RNL, anti-Mullerian hormone (AMH), gonadotropin, androgen levels, and metabolic parameters were investigated. Plasma-free NMN and NGF concentrations were increased in PCOS individuals, while RNL levels were decreased compared to healthy volunteers. Increased plasma-free NMN (OR = 1.0213 [95%CI 1.0064-1.0364], p = 0.005) and NGF (OR = 1.0078 [95%CI 1.0001-1.0155], p = 0.046) but not MN or RNL levels were associated with a higher risk of PCOS after adjustment for age. Plasma-free NMN levels were positively associated with the LH (r = +0.253; p = 0.039). androstenedione (r = +0.265; p = 0.029), 17-OH progesterone (r = +0.285; p = 0.024), NGF (r = +0.320; p = 0.008), and AMH (r = +0.417; p < 0.001) concentrations of the investigated women. RNL levels were inversely related to the BMI (r = -0.245; p = 0.029), HOMA-IR (r = -0.250; p = 0.030), free testosterone (r = -0.303; p = 0.006) levels. systolic (r = -0.294; p = 0.008) and diastolic (r = -0.342; p = 0.002) blood pressure. Increased sympathetic noradrenergic activity and NGF synthesis might be related to the increased AMH and delta-4 androgen levels in a subgroup of PCOS patients. RNL levels might influence the metabolic status of PCOS patients. Further studies are needed to explore the significance of adrenal medullar and autonomic dysfunction for developing different PCOS phenotypes and their subsequent cardiovascular complications.

Imaging and pathologic correlation of composite pheochromocytoma-ganglioneuroma.

A 50-year-old man consulted our institution for headaches and uncontrolled high blood pressure. Laboratory work-up and endocrine evaluation were consistent with pheochromocytoma with elevated plasma free metanephrine, free normetanephrine, plasma epinephrine, norepinephrine, total catecholamines, and 24-hour urine fractionated metanephrines, normetanephrines and total metanephrines levels. CT showed a contrast-enhancing 11.5 × 12.4 × 8.8 cm right adrenal complex cystic mass (Fig. 1A). Subsequent 68Ga-DOTATATE PET/CT confirmed the large right adrenal lesion with prominent tracer avidity (Fig. 1B). Surgical resection and pathology (Figs. 1C and 2) reached the diagnosis of composite pheochromocytoma-ganglioneuroma (CPG). The patient’s symptoms resolved after surgery. Genetic testing was normal. CPG, a rare tumor of mostly third-to-fifth decade of life with no gender preference, contains both pheochromocytoma (PC) and ganglioneuroma (GN) neoplastic components. CPG features symptoms of catecholamine overproduction: headache, palpitations, hypertension, and diaphoresis, and abdominal pain and watery diarrhea from excess VIP production by ganglioneuroma cells. CPG is indistinguishable from PC by clinical presentation, imaging features and biomarkers. Most CPG patients present with elevated catecholamines (1,2). CPG appears on CT as a well-circumscribed, heterogeneous or cystic adrenal mass with contrast enhancement. 68Ga-DOTATATE PET/CT may be an effective functional imaging modality for the detection and post-surgical monitoring of CPG based on its PC component (2). Diagnosis is histological with the identification of admixed regions of usually dominant PC and GN. PC cells stain positively for synaptophysin, GN cells with NeuN and Schwann cells with S-100. BRAF and HRAS mutations are frequently associated with CPG (3). CPG resection proceeds like PC surgery with preoperative adrenergic blockade, increased oral hydration and salt supplementation. The overall risk of malignancy associated with CPG is notably lower than with pure PC. Symptoms usually resolved upon CPG surgical resection, as seen in our case. One-out-of-eight treated patients may develop recurrence within 15 months (1).

Validation of Vanillylmandelic Acid (VMA) with Plasma Metanephrine and Normetanephrine for Screening Adrenal Medullary Disorders

Objective: To validate urinary Vanillylmandelic acid (VMA) for screening adrenal medullary disorders, taking plasma-free Metanephrine as the gold standard.&#x0D; Study Design: Cross-sectional validation study.&#x0D; Place and Duration of Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology,Rawalpindi, in collaboration with Armed Forces Institute of Urology, Rawalpindi from Pakistan, Jan 2020 to Mar 2021.&#x0D; Methodology: One hundred and thirty (130) symptomatic hypertensive patients with adrenal masses on ultrasound were selected Urine and blood samples were collected under specified conditions after taking necessary precautions and subsequently analyzed. Taking plasma Metanephrine as a reference, sensitivity, specificity and predictive values were calculated at predefined cut-off values. &#x0D; Results: In a young population with a mean age of 28.55±5.54 years, headache, palpitations and sweating were the predominant symptoms having a frequency of 130(100%), 116(89.2%) and 111(85.4%), respectively. Twenty-four hours urinary Vanillylmandelic acid had lower sensitivity (66.3%) than a random urinary VMA/cr ratio (72.1%) but similar specificity(97.7%). On the other hand, plasma-free Normetanephrine had 100% sensitivity but lower specificity (93.2%). ROC curve was plotted, and AUC for 24 hours urinary VMA, urinary VMA/cr ratio and plasma-free Normetanephrine were 0.820, 0.849 and0.966, respectively.&#x0D; Conclusion: Plasma-free Metanephrine could be used for screening pheochromocytoma and other adrenal medullary disorders like paraganglionoma. In addition, VMA/cr ratio can be used for biochemical confirmation of the disease owing to the high specificity found in our study.

Reference intervals for plasma, urinary, and salivary concentrations of free metanephrines in dogs: Relevance to the diagnosis of pheochromocytoma.

Measurement of free metanephrines is recommended for screening of pheochromocytoma (PCC) but requires appropriate reference intervals (RIs). To report RIs for plasma, urinary and salivary concentrations of free metanephrines and to determine the diagnostic performance of plasma free normetanephrine (pNMN) and metanephrine (pMN) concentrations in dogs with PCC, hypercortisolism (HC), and nonadrenal illness (NAI). Eighty healthy dogs, 11 PCC dogs, 25 HC dogs, 6 NAI dogs. Plasma, urine, and saliva were collected prospectively from healthy dogs, and free metanephrine concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, medical records of dogs that had plasma free metanephrine concentrations measured by LC-MS/MS between 2018-2021 were studied retrospectively. The RIs for free metanephrines in plasma, urine and saliva are reported. Dogs with PCC had significantly higher pNMN than dogs with HC (P< .001) and NAI (P= .002). The PCC dogs had significantly higher pMN than HC dogs (P< .001), but not higher than NAI dogs (P= .29). Using the upper reference limit, pNMN (>3.56 nmol/L) showed high sensitivity (100%, 95% confidence interval [CI]: 72-100) and specificity (94%, 95% CI: 79-99) for diagnosis of PCC, whereas pMN (>2.49 nmol/L) showed moderate sensitivity (73%, 95% CI: 39-94) and high specificity (94%, 95% CI: 79-99). With establishment of these RIs, biochemical testing for PCC in dogs can be substantially improved. Measurement of pNMN is superior to pMN in dogs with PCC.

PS-BPR01-8: A CASE OF PHEOCHROMOCYTOMA WITH CONCOMITANT SPLENIC ARTERY ANEURYSM

A 62-year-old man with a 30-year history of headaches and a 20-year history of treatment-resistant hypertension and diabetes mellitus was referred to our hospital for evaluation of his 5 cm retroperitoneal tumor found by abdominal ultrasound examination at a medical checkup. A simple CT and MRI scan showed a heterogeneous tumor (diameter, 5 cm) in the left adrenal gland and a splenic artery aneurysm (diameter, 2 cm). Endocrine examinations revealed increased levels of plasma-free normetanephrine (NMN) (853 pg/mL), urinary noradrenaline (NA) (670 μg/day), and urinary NMN (2.6 mg/day). 123I-MIBG scintigraphy showed high accumulation in the left adrenal region. He was diagnosed with NA-dominant left pheochromocytoma. His blood pressure was controlled at around 140/90 mmHg with 16 mg of doxazosin and 10 mg of amlodipine. His insulin-dependent diabetes was treated with multiple daily insulin injections (63 units/day), metformin, and miglitol. First, he underwent splenic artery aneurysm embolization under general anesthesia, which was completed without developing a hypertensive crisis. Two months later, he underwent laparoscopic left adrenalectomy, and the resected tumor was pathologically diagnosed as pheochromocytoma with a GAPP score of 1. He did not develop postoperative hypotension. His blood pressure was well controlled with only 10 mg of amlodipine, and his insulin requirement was reduced to 23 units/day after surgery. Since few cases of pheochromocytoma with concomitant splenic artery aneurysm have been reported, we discussed the treatment plan with much consideration. Splenic artery aneurysms have a high risk of rupture due to intraoperative blood pressure elevation in pheochromocytoma, which could be fatal. Although the first choice of treatment for a splenic artery aneurysm is endovascular therapy, the use of contrast media is generally contraindicated in pheochromocytoma in Japan due to the risk of hypertensive crisis. In the present case, systemic management with a sufficiently high dose of alpha-blocker allowed the embolization to be preceded avoiding a crisis, and subsequent surgery for pheochromocytoma could be performed safely. A long history of hypertension and diabetes exacerbated by the pheochromocytoma may have contributed to the arteriosclerosis leading to the splenic artery aneurysm. Here we report a rare case of pheochromocytoma with concomitant splenic artery aneurysm and will discuss the pathogenesis and management of this case with a review of the literature.

ODP549 From Positive to Negative, a Histidine to Aspartic Acid Change in SDHB is Breaking Bad in Cardiac Paraganglioma

Abstract Introduction Cardiac paraganglioma (PGL) are extremely rare tumors. They are derived from chromaffin cells of the neural crest. Up to 40% of PGL foster germline mutations, while some bear somatic mutations. Here, we describe a sympathetic paraganglioma presenting as a cardiac mass, found to have a novel mutation of SDHB. Clinical Case A 64-year-old man with uncontrolled type 2 diabetes mellitus presented with chest pain, progressive fatigue and unintentional weight loss. An echocardiogram demonstrated a right atrial mass. Cardiac magnetic resonance imaging showed a 6.9×5.8×4.9 cm mass in the lateral right atrial wall and right atrioventricular groove, encasing the right coronary artery. Surgical removal was attempted and aborted due to involvement of the tricuspid valve. Incisional biopsy was consistent with paraganglioma. Plasma free normetanephrine was elevated at 1.87 nmol/L (ULN 0.89 nmol/L) and plasma free metanephrine was normal at 0.14 nmol/L (ULN 0.49 nmol/L). Chromogranin A was elevated at 1,038 ng/mL (normal &amp;lt;93 ng/mL). Iodine-123 meta-iodobenzylguanidine scan demonstrated increased and persistent MIBG activity of the cardiac mass. Ga-68 DOTATATE PET/CT scan revealed DOTATATE avidity of the mass without evidence of distant metastatic disease. Next-generation sequencing of the specimen revealed a variant of unknown significance of SDHB H244D at a variant allele frequency of 62.2%. This missense mutation replaces the histidine to aspartic acid, resulting in changes in charge of the side chain from positive to negative. Systemic treatment with tyrosine kinase inhibitor (TKI) cabozantinib was initiated due to unresectable tumor. Three month surveillance with Ga-68 PET/CT DOTATATE scan revealed partial response to treatment. Chromogranin A and normetanephrine are trending down, suggesting biochemical response. Conclusion Cardiac PGL are rare and SDHB mutations are associated with worse prognosis. This is the first case of a missense mutation of SDHB at H244D, which may be clinically relevant in characterizing cardiac paraganglioma and potential response to TKI therapy. Presentation: No date and time listed

PSUN375 What Blindness and Paraganglioma Have in Common? A Rare Case of Paraganglioma Syndrome

Abstract Background Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with an annual incidence in the U.S. of 500-1600 cases per year. Approximately 30-35% of PPGLs harbor germline mutations, while 35-40% are due to somatic mutations. Recent studies have identified the association between somatic mutations of the hypoxia-inducible factor 2 alpha (HIF2A) gene and a new syndrome of PPGLs associated with congenital polycythemia. Patients present with recurrent PPGLs, congenital malformation of intracranial veins, malformation of macula and retina, and type I Chiari malformations. Case A 44-year-old man with history of in-utero stroke, congenital blindness, polycythemia and spinal stenosis had an incidental para-aortic lesion found during workup of back pain. He experienced episodic palpitations associated with diaphoresis, headache and uncontrolled hypertension for the past eight year. There was no family history of neuroendocrine tumors. Dedicated abdominal computer tomography with contrast showed a right adrenal enhancing lesion measuring 1.4×1.2 cm and a conglomerate of heterogenous enhancing periaortic lesions measuring up to 5 cm in the mid-abdomen. Biochemical work up revealed plasma free normetanephrine of 27.5 nmol/L (0.00-0.89) and plasma free metanephrines of 0.49 nmol/L (0.00-0.49). Gallium 68 DOTATATE scan showed multiple avid retroperitoneal lesions measuring up to 4.4 cm and an avid right adrenal nodule. He underwent right adrenalectomy and para-aortic lesion resection with perio-operative alpha blockade. Pathology confirmed synchronous pheochromocytoma (1.5 cm, Ki-67&amp;lt; 1%, with capsular and periadrenal fat invasion) and paraganglioma (9.3 cm, Ki-67 &amp;lt; 1%, with lymphovascular invasion and one out of nine lymph nodes positive for metastatic disease). Post-operatively, his metanephrines normalized and a six-months positron emission tomography scan showed no evidence of disease. Genetic testing has been delayed. Discussion This case illustrates a rare syndrome of PPGLs, congenital blindness, and polycythemia, likely due to somatic mutations of HIF2a. HIF is an alpha/beta heterodimer. HIF2a becomes a transcription factor after dimerization with HIF2b. Any mutations that stabilize HIF protein leads to transcription of hypoxia inducible genes resulting in angiogenesis, polycythemia, and tumorigenesis. In our patient, we suspect the stroke in-utero may have been related to abnormal intracranial angiogenesis and/or polycythemia. Recognition of this syndrome and lifelong surveillance is imperative due to risk of recurrence of PPGL. Targeted therapies such as a HIF2a inhibitor have been proposed and trials are ongoing. Our patient remains disease free on radiographic and biochemical surveillance. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Dual-Template Magnetic Molecularly Imprinted Polymer for Simultaneous Determination of Spot Urine Metanephrines and 3-Methoxytyramine for the Diagnosis of Pheochromocytomas and Paragangliomas.

A novel dual-template magnetic molecularly imprinted polymer (MMIP) was synthesized to extract normetanephrine (NMN), metanephrine (MN) and 3-methoxytyramine (3-MT) from spot urine samples. As the adsorbent of dispersive solid-phase extraction (d-SPE), the MMIP was prepared using dopamine and MN as dual templates, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the crosslinking reagent and magnetic nanoparticles as the magnetic core. NMN, MN, 3-MT and creatinine (Cr) in spot urine samples were selectively enriched by d-SPE and detected by HPLC-fluorescence detection/ultraviolet detection. The peak area (A) ratios of NMN, MN and 3-MT to Cr were used for the diagnosis of pheochromocytomas and paragangliomas (PPGLs). The results showed that the adsorption efficiencies of MMIP for target analytes were all higher than 89.0%, and the coefficient variation precisions of intra-assay and inter-assay for the analytes were within 4.9% and 6.3%, respectively. The recoveries of the analytes were from 93.2% to 112.8%. The MMIP was still functional within 14 days and could be reused at least seven times. The d-SPE and recommended solid-phase extraction (SPE) were both used to pretreat spot urine samples from 18 PPGLs patients and 22 healthy controls. The correlation coefficients of ANMN/ACr and AMN/ACr between d-SPE and SPE were both higher than 0.95. In addition, the areas under the receiver operator curves for spot urine ANMN/ACr, AMN/ACr and plasma free NMN and MN were 0.975, 0.773 and 0.990, 0.821, respectively, indicating the two methods had the similar performances. The d-SPE method took only 20 min, which was effective in clinical application.

Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine.

Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results. 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined. Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R ≥ 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2% (-11.6% to 16.0%) for metanephrine and 0.1% (-18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine. Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.

177Lu-DOTATATE therapy in metastatic/inoperable pheochromocytoma-paraganglioma.

Introduction:177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising therapy for metastatic and/or inoperable pheochromocytoma and paraganglioma (PPGL). We aim to evaluate the efficacy and safety of and identify predictors of response to 177Lu-DOTATATE therapy in metastatic and/or inoperable PPGL.Methods:This retrospective study involved 15 patients of metastatic or unresectable PPGL, who received 177Lu-DOTATATE PRRT therapy. Clinical, biochemical (plasma-free normetanephrine), and radiological (anatomical and functional) responses were compared before and after the last therapy.Results:A total of 15 patients (4 PCC, 4 sPGL, 5 HNPGL, 1 PCC + sPGL, 1 HNPGL + sPGL) were included. The median duration of follow up was 27 (range: 11–62) months from the start of PRRT. Based on the RECIST (1.1) criteria, progressive disease was seen in three (20%), stable disease in eight (53%), partial response in one (7%), and minor response in three (20%) and controlled disease in 12 (80%). On linear regression analysis the presence of PGL (P= 0.044) and baseline SUVmax >21 (P < 0.0001) were significant positive predictors of early response to PRRT. Encouraging safety profiles were noted with no long term nephrotoxicity and hematotoxicity.Conclusion:177Lu-DOTATATE therapy is an effective and safe modality of treatment for patients with metastatic/inoperable PPGL. Although it is not prudent to withhold PRRT in metastatic PPGL with baseline SUVmax < 21, baseline SUVmax >21 can be used to predict early response to PRRT.

MON-384 The Dynamic Genetics of Recurrent Paragangliomas: The Importance of Surveillance

BACKGROUND: Paraganglioma (PGL) are tumors that arise from the ganglia of the sympathetic nervous system, and comprise 10% of all sympathetic nervous system tumors. There are at least 16 germline mutations that have been associated with increased risk of PGL. CASE PRESENTATION: A 32 year-old female with a history of PGL status-post resection presented with elevated plasma metanephrines during surveillance follow-up. She was diagnosed with PGL 7 years ago. Plasma free normetanephrine were elevated at 607 pg/ml (ref ≤ 148 pg/ml) and an MRI abdomen demonstrated a 6.6 x 4.5 x 7.8 cm para-aortic retroperitoneal mass. An MIBG scan showed no abnormal activity. She underwent resection of PGL. Postoperative labs showed normal plasma and urine metanephrines. Genetic testing was negative for known related mutations. She reported dizziness and palpitations six years later. Labs revealed elevated free normetanephrine 213 pg/ml and total metanephrine 238 pg/ml (ref ≤ 205 pg/ml). Repeat plasma and urine tests remained elevated, but an MRI abdomen/pelvis and two MIBG scans were unremarkable. The patient remained symptomatic. Six months later, CT abdomen/pelvis showed a retroperitoneal 2.5 x 1.8 x 1.7 cm necrotic mass and an 3.2 x 2.6 x 2.5 cm adnexal cystic lesion concerning for recurrent PGL. Repeat testing confirmed elevated plasma free normetanephrine 511 pg/ml and undetectable free metanephrine. PET/CT abdomen/pelvis demonstrated the retroperitoneal necrotic mass, two lesions anterior to the L3 and L4-L5 vertebral bodies, and a lytic lesion in the right iliac crest. The patient underwent surgical resection of three PGL, all with vascular and capsular invasion. Six months later, plasma and urinary levels were all normal. PET Ga-68 DOTATATE scan demonstrated uptake near the surgical bed and in the aorto-caval groove, suspicious for residual tumors, and several foci of somatostatin receptor positive osseous lesions, suspicious for skeletal metastases. An updated genetic test showed a variant of uncertain significance (VUS) of the SDHA gene. She is currently undergoing treatment with lanreotide. CONCLUSION: This case highlights the importance of continuous surveillance, as well as the swift advancements in genetics associated with paragangliomas and pheochromocytomas. REFERENCES: Fishbein, L.,et al. (2013). Inherited Mutations in Pheochromocytoma and Paraganglioma: Why All Patients Should Be Offered Genetic Testing. Annals of Surgical Oncology, 20(5),1444-1450.

SAT-317 The Importance of Accurate Genetic Diagnosis Highlighted in a Case of Recurrent Bilateral Pheochromocytomas

Background It is estimated that one-third of patients with pheochromocytomas and paragangliomas (PPGL) have germline mutations. This patient with bilateral pheochromocytomas was initially diagnosed with MEN2A syndrome, underwent prophylactic total thyroidectomy, only to be diagnosed with a different germline mutation subsequently. Clinical case This patient first presented at 12 years of age, with hypertensive emergency and a right 8cm adrenal tumour with spontaneous haemorrhage. He underwent emergency right adrenalectomy, with histology confirming a pheochromocytoma. Post-operatively, urinary metanephrines were normal and symptoms resolved. 7 years later, he re-presented with headache, postural hypotension, cutaneous lichen amyloidosis and elevated urinary normetanephrine (NMT). CT abdomen showed 2 left adrenal masses with no residual right adrenal lesion. Open left adrenalectomy was performed and 3 pheochromocytoma nodules of 8 to 10mm in size were found. Urinary NMT was normal post-surgery. He was commenced on hydrocortisone and fludrocortisone replacement. In view of his young age and bilateral pheochromocytomas, genetic testing was done. RET proto-oncogene testing showed a silent mutation in Exon 13 Codon 769 CTT->CTG coding for Leucine, suggestive of MEN2A syndrome. His calcium and parathyroid hormone were normal. Although asymptomatic, he underwent prophylactic total thyroidectomy. However, histology revealed no endocrine cell hyperplasia. At age of 33 years, his symptoms recurred. Plasma free NMT was raised, 3.29nmol/L (reference <0.71nmol/L), while plasma metanephrine and 3-methoxytyramine were normal. Ga68-DOTAPEPTIDE PET/CT showed one tracer-avid lesion in each adrenal bed, suspicious of recurrent bilateral disease. He underwent open bilateral adrenalectomy and histology confirmed bilateral recurrent pheochromocytomas. Post-operatively, his plasma NMT has normalised. His atypical presentation for MEN2A syndrome prompted a repeat hereditary PPGL genetic testing. A pathogenic variant in the SDHD gene, namely c.3G>C (Initiator codon) was identified, while his previous MEN2A mutation of indeterminate significance was deemed not pathogenic. His father subsequently tested positive for SDHD mutation and is undergoing further investigations. Conclusion Major advances in the understanding of hereditary PPGL have been made over the last decade. Identification of the correct germline mutation is important to predict risks of malignancy, recurrence and guide early treatment. This case highlights the importance of comprehensive, targeted genetic testing with trained geneticist over traditional single gene tests and the need to interpret results with caution. Reference Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. Jacques W.M. Lenders et al. J Clin Endocrinol Metab.2014; 99 (6): 1915-1942.

Age-specific pediatric reference intervals for plasma free normetanephrine, metanephrine, 3-methoxytyramine and 3-O-methyldopa: Particular importance for early infancy

BackgroundAvailability of appropriately established reference intervals for biochemical tests can be troublesome in pediatrics. Here we establish age-specific continuous reference intervals for catecholamine O-methylated metabolites in children evaluated for catecholamine producing tumors, particularly younger children with suspected neuroblastoma. MethodsPlasma concentrations of 3-methoxytyramine, normetanephrine, metanephrine, and 3-O-methyldopa were analyzed by liquid chromatography tandem mass spectrometry in 533 children aged 2 days to 18 years. ResultsConcentrations of plasma free normetanephrine, 3-methoxytyramine and 3-O-methyldopa were higher in neonates up until six months of age, but thereafter declined steeply to levels after one year that were <38% those of neonatal concentrations and to further lower concentrations in teenagers that were <23% those in neonates. In contrast, concentrations of plasma free metanephrine showed a reciprocal pattern with 50% lower concentrations in infants below one year compared to later in childhood. ConclusionThe dynamic reciprocal changes in plasma concentrations of normetanephrine, 3-methoxytyramine and 3-O-methyldopa compared to metanephrine during early childhood suggest underlying developmental changes in extra-adrenal and adrenal chromaffin tissue that must be considered for pediatric reference intervals, particularly in infants. With such reference intervals at hand, biochemical testing for catecholamine producing tumors in young children is substantially improved.

Sympathetic Paraganglioma: A Single-Center Experience from Western India

Most of the Indian studies on pheochromocytoma/paraganglioma (PCC/PGL) have focused on PCC, and there is a paucity of information regarding sympathetic paraganglioma (sPGL). Here, we describe the clinical, biochemical, and imaging features of sPGL compared with PCC. This retrospective study included 75 patients with sPGL and 150 patients with PCC. Diagnosis of PCC/PGL was based on surgical histopathology, and if histopathology was not available, on biochemistry and/or radiology. sPGL was more frequently detected incidentally ( P = .03), normetanephrine-secreting ( P<.01), and metastatic compared with PCC ( P≤.01). sPGL was most commonly located in the organ of Zuckerkandl (OOZ) (49%) and infradiaphragmatic area above the OOZ (27%). Patients with mediastinal sPGL were significantly older than those with sPGL in the OOZ ( P = .03). Primary tumors of metastatic sPGL were significantly larger than those without metastasis (7.8 ± 4 cm vs. 5.6 ± 3.2 cm; P = .004). Percentage arterial enhancement (PAE) >100% was seen in 98% of sPGLs. Incidental presentation, normetanephrine-secreting phenotype, and metastatic disease were more frequent in patients with sPGL than those with PCC. sPGL arose most commonly in the OOZ. Tumor size is an independent predictor of malignancy among sPGL patients. PAE >100% is almost a universal finding in sPGL, and its absence is a sensitive parameter to differentiate sPGL from other abdominal masses. AP = arterial phase; CECT = contrast-enhanced computed tomography; CT = computed tomography; DP = delayed phase; EVP = early venous phase; FDG = fluorodeoxyglucose; fPFMN = fractionated plasma free metanephrine; HU = Hounsfield units; MIBG = metaiodobenzylguanidine; MRI = magnetic resonance imaging; OOZ = organ of Zuckerkandl; PAE = percentage arterial enhancement; PCC = pheochromocytoma; PET = positron emission tomography; PFNMN = plasma free normetanephrine; PGL = paraganglioma; PRRT = peptide receptor radionuclide therapy; PVE = percentage venous enhancement; sPGL = sympathetic paraganglioma; UP = unenhanced phase; VMA = vanillyl mandelic acid.

Concurrent primary hyperparathyroidism and pheochromocytoma in a Chinese lady with neurofibromatosis type 1.

SummaryWe report a case of elderly Chinese lady with neurofibromatosis type-1 presenting with longstanding palpitation, paroxysmal hypertension and osteoporosis. Biochemical testing showed mild hypercalcaemia with non-suppressed parathyroid hormone level suggestive of primary hyperparathyroidism, and mildly elevated urinary fractionated normetanephrine and plasma-free normetanephrine pointing to a catecholamine-secreting pheochromocytoma/paraganglioma. Further scintigraphic investigation revealed evidence of a solitary parathyroid adenoma causing primary hyperparathyroidism and a left pheochromocytoma. Resection of the parathyroid adenoma and pheochromocytoma resulted in normalization of biochemical abnormalities and hypertension. The rare concurrence of primary hyperparathyroidism and pheochromocytoma in neurofibromatosis type-1 is discussed.Learning points:All NF-1 patients who have symptoms suggestive of a pheochromocytoma/paraganglioma (PPGL), even remotely, should undergo biochemical testing.The initial biochemical tests of choice for PPGL in NF-1 are either plasma-free metanephrines or urinary fractionated metanephrines. Any elevations of metanephrines should be carefully evaluated for the presence of PPGLs in NF-1 patients.Primary hyperparathyroidism (PHPT) is described in subjects with NF-1. Due to the lack of epidemiological and functional studies, their association is yet to be substantiated. Meanwhile, PHPT may further exacerbate the metabolic bone defect in these patients and should be treated when present according to published guidelines.Coexistence of PPGL and PHPT can occur in subjects with NF-1, mimicking multiple endocrine neoplasia type 2 (MEN2).